Author Topic: 3-Propananilidotropanes  (Read 6906 times)

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  • Guest
« on: October 12, 2002, 04:24:00 AM »
Synthetic overview

Consider the tropinone molecule.

When the ketone reacts with aniline, an imine is formed.  This tropananil compound can be reduced to give an anilino-tropane, which can be acylated with propionic anhydride to give a N-propananilido-tropane.


Don't worry: I will follow an intuitive approach on this in order to explain the rather complicated nomenclature.

When you look at the tropinone molecule, you see that there are in fact 2 ring systems.  A 5 membered N-methyl pyrrolidine ring which is "fused" to a 6 membered N-methyl 4-piperidone ring.  The 6 membered ring is like cyclohexane, in its chair conformation: at one end the N-CH3 points upwards and at the other end the C=O points downwards.  Concentrate now on the 6 membered ring.  When the tropananil is reduced, 2 isomeres can be formed.  The compound where the -NH-Ph points downwards is called  3alpha-anilino-1alphaH,5alphaH-tropane (1).  And the product where the -NH-Ph points upwards is called 3beta-anilino-1alphaH,5alphaH-tropane (3).
Acylation of (1) provides 3alpha-(N-propananilido)-1alphaH,5alphaH-tropane (2).  And - guess what - when (3) reacts with propionic anhydride, 3beta-(N-propananilido)-1alphaH,5alphaH-tropane (4) is obtained.

What the hell is the purpose of all this?

The attentive reader will see a resemblence with fentanyl.  Focus again on the 6 membered ring: at one end there is a N-methyl group instead of a N-phenethyl group.  At the other end, there is the (for the fentanyl family of compounds caracteristic) N-propananilido group.  There is no single hair on my head that doubts that these compounds will be powerfull narcotics (although not as powerfull as fentanyl).  These compounds have like a combination of the meperidine, fentanyl and cocaine structural features.


The alpha-compound:


A solution of 30 g (0.215 mole) of tropinone and 40 g (0.52 mole) of aniline in 250 ml of toluene was refluxed with stirring over 90 g of 4A molecular sieves for 24 hours.  The solution was cooled, filtered and concentrated in vacuo yielding a thick dark oil (the tropananil).  A solution of tropananil in 100 ml of absolute EtOH was treated with 0.8 g of PtO2 and the mixture was hydrogenated at 3 atm. until the calculated amount of hydrogen was consumed.  The mixture was filtered and concentrated in vacuo and the resulting oil was distilled (132 - 141 °C / 0.6 mm Hg) to provide 14.4 g (31 %) of (1).  The distilled oil solidified upon standing and rectrystallized from petroleum ether, m.p.: 68 - 71 °C
This is an isomerically pure product.


A solution of 1 g (0.0046 mole) of (1) in 13 ml of propionic anhydride was refluxed for 24 hours.  The reaction was cooled, diluted with 200 ml of ether and threated with 10 % NaOH for 15 minutes.  The ether layer was separated, dried over MgSO4, concentrated in vacuo and the residual oil distilled (170 - 175 °C / 0.10 mm Hg) providing 0.97 g (77 %) of (2).
The HCl salt of (2) is made from an EtOH -Et2O mixture, m.p.: 196 - 197 °C.

The beta-compound:


A solution of tropananil, prepared as described above from 9.9 g (0.071 mole) tropinone and 18.0 g (0.194 mole) of aniline, was dissolved in 100 ml of absolute EtOH and 6.6 g (0.28 g-atom) of Na pieces were added over a 10 minute period.  The reaction was then refluxed for 3.5 hours.  The reaction was cooled and poured into 100 ml of ice water and extracted with 2 x 100 ml portions of ether.  The etheral solution was dried over MgSO4, concentrated in vacuo and the residual oil distilled (130 - 135 °C / 1 mm Hg).  The distillate solidified upon standing yielding 3.2 g (21 %) of a mixture of isomers.  Glc showed a 70:30 mixture of the beta-isomer and the alpha-isomer.  Recrystallization of the isomer mixture from petroleum ether yielded 1.8 g (12 %) of pure (3), m.p.: 105 - 107 °C


Treatment of 1 g (0.0046 mole) of (3) with 13 ml of propionic anhydride as described above provided 0.83 g (66
%) of (4) (b.p.: 220 - 222 °C / 0.5 mm Hg)
The HCl salt of (4) is made from an EtOH -Et2O mixture, m.p.: 172 - 173 °C.

Ref.: J. Heterocyclic Chem. (1977) vol 14 p 599

It's a shame - although interesting - that the article is especially concerned with NMR analysis.  Hence the desire to prepare isomerically pure compounds.  They 'd better give the results of the pharmacological evaluation of this compound.

Synthetic improvements for bees

* The acylation conditions they use are really a joke: propionic anhydride as a solvent  ::)  ::)  ::) .  Are those dudes nuts?
They 'd better use an equimolar amount (or a slight excess) of propionyl chloride and do the reaction in chloroform - like I said in

Post 342512 (missing)

(Cyrax: "If propionic anhydride is not reactive enough to ...", General Discourse)
.  Another advantage of this approach is that the HCl salt will be generated in situ, since the N-CH3 captures the during the reaction liberated HCl.

* The yields of the imine reduction would be considerably better if you use a procedure à la Labtop.  Throw a 4A molecular sieves in the mixture of tropinone and aniline, so that the sieves absorb the H2O that is liberated during the imine formation.  And then add NaBH4 to reduce the tropananil.  I guess the reaction shall not be stereoselective, but who cares.  This would be a one pot reaction. 

* A synthesis of tropinone can be formed at:

The original procedure used by Robinson is described in JACS (1917) vol 111 p 762 - 768.

Dreaming your narcotic dreams.


  • Guest
Interesting Idea makes a comeback I see...
« Reply #1 on: October 12, 2002, 01:30:00 PM »
Drone 342 had this idea a long while back. His novel synthesis started from atropine (poison of nightshade).

The discussion is both here at the Hive, and also archived at Rhodium's site under the fentanyl documents I believe.  :)


Firm supporter of the "Purge The Couch!" movement. Vote for the purge today.


  • Guest
« Reply #2 on: October 12, 2002, 04:05:00 PM »
Indeed, the post of Drone 342 inspired me to elaborate the idea.

But I guess the problem with the deadly nightshade is that you will extract a bunch of other alkaloids together with the atropine.

I wonder, is Drone 342 still around here?   His account doesn't seem to be active any more.  Otherwise, I would have thanked him personally.

Dreaming your narcotic dreams.


  • Guest
Droneamine Revisited
« Reply #3 on: October 13, 2002, 02:48:00 AM »
This sounds like a VERY interesting scheme. However, we need to find the references Drone was talking about regarding substituting that N-methyl with a N-benzyl or N-Phenethyl group, as the compound above is inactive below 100mg/kg. An alterbative is to react the N-methyl with cyanogen bromide, and then re-alkylate.

The hydrochlorides of the alpha/beta forms of the N-Benzyl compound are active at 35.5/1.8 mg/kg and the corresponding  N-Phenethyl compounds are active at 2.22/0.047 mg/kg, compared to 0.024 mg/kg for plain Fentanyl citrate.

Reference: J. Med. Chem. 22, 1167 (1979) -

Drone is no longer around. He found out that the world of clandestine chemistry was a little bit too exciting, after having had close calls on more than one occasion. He now lives happily as an organic chemist employed at a research company.


  • Guest
The ref. that Drone 342 has provided seems very ...
« Reply #4 on: October 13, 2002, 02:17:00 PM »
The ref. that Drone 342 has provided seems very interesting:
 Chem.Heterocycl.Compd.; 21; 12; 1985; 1355-1362

I 'll see if I can find it when I fool around in the library this week - but I fear they don't have that journal  :( .

Mabey it would be more efficient to make it directly, replacing methylamine by phenethylamine in the Robinson tropinone synthesis (which is essentially a double Mannich reaction).  However, I don't know if the reaction conditions would allow this modification since I haven't got an article about the subject.

Cyanogen bromide is a little bit too dangerous for this bee.  It was used by the Austrians in the past as a chemical warfare agent ... (although cyanogen chloride would be a better alternative for this purpouse, since it's a gas at room temperature).

Rhodium, thanks for posting the JMC article.  It was just the pharmacological evaluation I was looking for  :) .


  • Guest
« Reply #5 on: January 26, 2004, 12:26:00 PM »
Synthesis and Conformational Analysis of Isomeric 3-Propananilidotropanes
Jerome R. Bagley and Thomas N. Riley

J. Heterocyclic Chem. 14, 599-602 (1977)


The isomeric 3-anilino and 3-propananilidotropanes have been synthesized and obtained in isomerically pure form. The configurations and solute conformations of these isomers were studied via glc and nmr analysis. The 3-beta-isomers have been shown to exist in the normal piperidine chair conformation whereas the 3-alpha-anilinotropane exists in a flattened piperidine chair conformation and the 3-alpha-propananilidotropane isomer preferentially exists in a conformation in which the piperidine ring system is a boat.